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Clinical Trials in India (30.8.2013)

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NOTE ON CLINICAL TRIALS IN INDIA

1. Research in the area of drug discovery leads to newer, safer and more efficacious drugs being made available in the country. Clinical trials are the only way of establishing the safety and efficacy of any new drug before its introduction in the market for human use. Clinical trials(with safeguards) are necessary for introduction of new drugs for a country like India, considering its disease burden and emergence of new variants of disease.

2. Clinical trials are, therefore, essential component of drug discovery research.  In order to generate adequate evidence to establish safety and efficacy of any substance for any specific indication, it is necessary that over and above all in vitroin vivo, and ex vivoexperimentations, the product is also administered to healthy volunteers and patients and clinically studied under a well-defined protocol to establish the safety and efficacy of a new drug.  This is a highly knowledge intensive activity generally carried out in international programmers.

3. The Drugs & Cosmetics Act, 1940 contains enabling provisions for regulating and ensuring quality, safety and efficacy of drugs and, therefore, contains inherent enabling powers for regulating the clinical trials. Accordingly, under the inherent plenary powers vested in the Act, necessary rules, procedures and guidelines have been framed under the Drugs and Cosmetics Rules, 1945. 

4. Regulatory provisions for conducting clinical trials in the country are prescribed under Rule-122DA, 122DAA, 122DAB, 122DAC. 122DD. 122E and Schedule Y to the Drug and Cosmetics Rules, 1945. The Clinical trial can be initiated only (i) after permission from the Drugs Controller General (India) [DCG(I)], (ii) approval from respective Ethics Committee and (iii) mandatory registration on website www.ctri.in being maintained by ICMR before the enrolment of the first trial participant for the clinical trial.

5. To ensure transparency in approval of proposals for conduct of clinical trials for drugs by the DCG(I), twelve New Drug Advisory Committees (NDAC) consisting of experts from the government medical colleges and eminent institutions from all over the country have been constituted.  Fresh applications of clinical trial proposals of new drug substances excluding investigational new drugs (INDs) are being evaluated by these Committees. For INDs, two separate expert committees have similarly been constituted. Similarly, for medical devices, six Medical Device Advisory Committees (MDAC) have been constituted.

6. The number of clinical trials permitted by DCG (I) in the last three years are as under:

Year

Number of clinical trial permissions granted

2010

529

2011

283

2012

253

7. As on 20-03-2013, as per the information available in www.clinicaltrials.gov of National Institute of Health, United States of America (USA), a total number of 1,42,239 clinical trials of different countries worldwide were registered.  Out of these, 67,881 are from USA, 38,473 from Europe, 10,702 from Canada, 2,645 from Japan.  Only 2,178 clinical trials were registered from India.

8. The Serious Adverse Events (SAEs) of death may occur during clinical trials due to various reasons. These deaths could be due to life-threatening diseases like cancer, cardio-vascular conditions like congestive heart failure / stroke and other serious diseases etc. Thus, all deaths during clinical trials may not be due to clinical trials. The number of SAEs of death in clinical trials, the number of deaths attributable to clinical trials and the number of cases, wherein compensation has been paid since 2005 are as follows:

Year

Total SAEs of Death

Death related to Clinical Trials

Compensation paid

2005

128

5

5

2006

137

2

0

2007

136

4

4

2008

288

8

7

2009

637

16

13

2010

668

22

21

2011

438

16

16

2012

436

16

16

In one case of 2010 the compensation remained unpaid as whereabouts of the legal heir could not be traced by the investigator and his team in spite of best efforts. The details of compensations paid are attached as Annexure.

9. Several steps have been taken by the Government, as follows, to strengthen the clinical trial approval procedures and their monitoring mechanism to ensure that safety, rights and well-being of clinical trial subjects are protected:

  •  12 New Drug Advisory Committees (NDAC) consisting of leading experts mostly from the Government medical colleges and institutes from all over the country have been constituted to advise the Central Drugs Standard Control Organisation (CDSCO) in matters related to approval of clinical trials and new drugs.
  • Applications of Investigational New Drugs (IND) i.e, New Drug Substances which have never earlier been used in human beings are evaluated by an IND Committee, chaired by the Director General, Indian Council of Medical Research (ICMR).
  • Registration of clinical trial in ICMR’s registry at www.ctri.in has been made mandatory.
  • Guidelines for conducting inspection of clinical trial sites and sponsor / Clinical Research Organizations (CROs) have been prepared.
  • Proposals to amend the toxicity study data requirements for  approval of clinical trial / new drugs to make it harmonized with the international guidelines have been approved by Drugs Technical Advisory Board (DTAB).

10.There have been several court cases in which issues relating to the deficiencies in the present legal provisions, safety of trial participants, death of trial participants, compensations for injury and death occurring in clinical trials, etc have been raised. Currently, the Hon’ble Supreme Court is hearing these matters in the Public Interest Litigation W.P.(C) No.33/2012 - Swasthya Adhikar Manch, Indore vs Union of India.          In the hearing of the matter on the 3rd January 2013, the Court directed that the clinical trials of new chemical entity shall be conducted strictly in accordance with the procedure prescribed in Schedule ‘Y’ of Drugs & Cosmetics Act, 1940 under the supervision of the Secretary, Health & Family Welfare. Accordingly, an Apex Committee under the chairmanship of the Secretary, Health & Family Welfare, with Secretary, Health Research-cum-Director General, Indian Council of Medical Research, and the Director General Health Services, has been constituted to monitor the approval and conduct of clinical trials.  In this connection, another Expert Committee under the chairmanship of Director General Health Services has also been constituted to assist the Apex Committee.

11. To further strengthen the regulatory provisions for approval of conduct of clinical trials and safety and well-being of trial participants, the Ministry of Health & Family Welfare has incorporated the following amendments recently in the Drugs & Cosmetics Rules, 1945:

A. Amendment vide Gazette Notification G.S.R. 53(E) dated 30-01-2013 specifying procedures to analyse the reports of Serious Adverse Events occurring during clinical trials and procedures for payment of compensation in case of trial related injury or death as per prescribed timelines as under:

I  Insertion of a new Rule 122DAB relating to compensation in case of injury or death during clinical trials.

(a)  As per the Rule, in the event of injury of the trial participant, he/she shall be provided free medical management by the sponsor or his representative as long as required.

(b)  In the event of injury or death due to following reasons which are considered as clinical trial related injury or death, the Sponsor or his representatives shall provide financial compensation for the injury or death.

  • Adverse effect of investigational product(s);
  • Violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;
  • Failure of investigational product to provide intended therapeutic effect;
  • Use of placebo in a placebo-controlled trial;
  • Adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
  • For injury to a child in utero because of the participation of parent in clinical trial;
  • Any clinical trial procedures involved in the study.

 II. Expansion of responsibilities of Sponsor, Investigator and Ethics Committees to ensure that the report of Serious Adverse Events (SAEs) including deaths are reported, analysed within the prescribed timelines and in case of clinical trial related injury or death, compensation are paid as per the prescribed procedures.

III. Insertion of definition of SAEs and detailed procedures for reporting and examination of such events in Schedule ‘Y’.

IV. The check list for trial participants’ informed consent documents have been amended to include statements describing that in the event of injury of the trial participant, he/she shall be provided free medical management as long as required and in the event of clinical trial related injury or death, the Sponsor or his representative shall provide financial compensation for the injury or death.

V.  The Format of Informed Consent Form for clinical trial participants have been amended to capture the information relating to address, qualification, occupation, annual income of the trial participant and name and address of his nominee (for the purpose of compensation in case of trial related death).  It has also been made mandatory for the investigator to hand over a copy of the patient information sheet and duly filled Informed Consent Form to the trial participant or his/her attendant.

VI.  Insertion of a separate Appendix XII related to compensation in case of injury or death during clinical trials in Schedule ‘Y’.  The Appendix prescribes the detailed procedures for examination of SAE reports including deaths and payment of financial compensation in case of trial related injury or death as per the prescribed timelines.

As per the procedures:-

(a)  Investigator shall report all SAEs to the DCG (I), Sponsor or his representative and the Ethics Committee within 24 hours of their occurrence.

(b)  In case of death, an independent Expert Committee constituted by DCG (I) shall examine the case and give recommendations to DCG (I) to determine the cause of death and also to decide the quantum of compensation, in case of clinical trial related death.  The independent Expert Committee, while examining the event, may take into consideration the reports of the Investigator, the Sponsor or his representative and the Ethics Committee.  The DCG (I), after considering the recommendations of the Expert Committee, shall determine the cause of death and decide on the quantum of compensation to be paid by the sponsor or his representative in case of trial related deaths within three months of receiving the report of SAE of death.

(c)  In case of SAEs other than death, the DCG (I), after considering the reports of the Investigator, the Sponsor and the Ethics Committee, shall determine the cause of injury and also decide the quantum of compensation to be paid by the Sponsor or his representative in case of clinical trial related injury within three months of receiving the report. The DCG(I) will have the option to constitute an Expert Committee to examine such SAEs and recommend the quantum of compensation to be paid, if any.

B. Amendment vide Gazette Notification G.S.R. 63(E) dated 01-02-2013 specifying various conditions for conduct of clinical trials, authority for conducting clinical trial inspections and actions in case of non-compliance, as under:

A new Rule 122DAC has been inserted, the salient features of which are as under:

  • Clinical trial shall be conducted in compliance with the approved protocols, requirements of Schedule Y, Good Clinical Practices (GCP) Guidelines for conduct of clinical trials in India and other applicable regulations;
  • Approval of the Ethics Committee shall be obtained before initiation for the study;
  • Clinical trial shall be registered at Clinical Trials Registry of India before enrolling the first patient for the study;
  • The Sponsor and his representative and clinical trial sites and the Investigator shall allow officers authorized by the Central Drugs Standard Control Organisation (CDSCO), who may be accompanied by an officer of the State Drug Control Authority concerned, to enter with or without prior notice into their premises and clinical trial sites to inspect, search and seize any record, data, document, books, investigational drugs, etc.
  • In case of non-compliance to the provisions of clinical trials by any Sponsor including the representative, investigators conducting clinical trial and clinical trial sites, DCG (I) can take following actions:

(a)  Reject or discontinue the study.

(b)  Suspend or cancel the clinical trial permission;

(c)  Debar the Investigator(s), Sponsor including his representative to conduct any clinical trial in future.

  1.    Amendments vide Gazette Notification G.S.R No. 72(E) dated 08-02-2013 specifying requirements and guidelines for registration of Ethics Committee, as under:

As per Rule 122DD:-

  1.               No Ethics Committee shall review and accord its approval to a clinical trial protocol without prior registration with DCG (I).
  1.              An application for registration of Ethics Committee is required to be made to DCG (I) along with detailed information about the committee as per Appendix VIII of Schedule Y, which include the Authority under which the committee has been constituted, details of qualification, etc of chairman and the members, procedures for replacement or removal of members, maintenance of records, Standard Operating Procedures (SOPs) to be followed by the committee for various activities like policy regarding training of members, prevention of conflict of interest, procedures for vulnerable population etc.
  1.             The Ethics Committee shall review and accord its approval to a clinical trial and also carry ongoing review of the trial at appropriate intervals, as specified in Schedule Y and the Good Clinical Practice Guidelines for Clinical Trials in India and other applicable regulatory requirements for safeguarding the rights, safety and well-being of the trial participants.

 

  1.             In the case of any serious adverse event occurring to the clinical trial participants during the clinical trial, the Ethics Committee shall analyse and forward its opinion as per procedures specified under Appendix XII of Schedule Y.

 

  1.              The Ethics Committee shall allow inspectors of officials authorized by the DCG (I) to inspect their facilities, records, documents etc.

 

  1.             The registration of an Ethics Committee shall be valid for a period of three years from the date of issue.

 

  1.            If the Ethics Committee fails to comply with any of the conditions of registration, DCG (I) may suspend or cancel the registration of the Ethics Committee.

12.       Since the Drugs & Cosmetics Act, 1940 does not contain specific provisions for regulating conduct of clinical trials and that the Act also does not have penal provisions therefor, specific provisions for the purpose were proposed in the Drugs & Cosmetics (Amendment) Bill, 2007 introduced in the Rajya Sabha on 21.8.2007. That Bill has been replaced by the Drugs & Cosmetics (Amendment) Bill, 2013 introduced on 29.8.2013, which contain more comprehensive provisions for the  purpose.

Annexure

             Details of compensation paid in the cases of clinical trial related deaths

Year 2005

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

 

Astra Zeneca

ZD1839

2,50,000

2

Sanofi

Heparin

3,00,000

3

Sanofi

Heparin

3,00,000

4

Roche

Bevacizumab

3,00,000

5

Siro

Methotrexate

2,55,450

Year 2007

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

Sanofi

Aflibercept

10,59,874

2

Sanofi

Aflibercept

3,00,000

3

Eli Lilly

Lisipro and Lantus

5,61,825

4

Eli Lilly

Pemetrexed

5,35,815

Year  2008

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

BMS

Ipilimumab

4,20,790

2

Bayer

Rivaroxaban

2,50,000

3

Bayer

Rivaroxaban

2,50,000

4

Bayer

Rivaroxaban

3,50,000

5

Bayer

Rivaroxaban

3,50,000

6

Bayer

Rivaroxaban

4,50,000

7

Clinigene

Bavituximab

5,00,000

Year 2009

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

 

Sanofi

AVE5026

3,00,000

 

Roche

Erlotinib

1,00,000

 

Allos Therapeutics

Pralatrexate

1,50,000

 

Boeringher Ingelheim

BIBF 1120

2,79,650

 

BMS

Apixaban

3,72,637

 

Sanofi

Aflibercept

1,13,750

 

Bayer

Rivaroxaban

3,50,000

 

Bayer

Rivaroxaban

3,50,000

 

Amgen

Denosumab

4,25,000

 

Sanofi

Aflibercept

2,00,000

 

Bayer

Rivaroxaban

3,50,000

 

Reliance

Sorafenib

5,00,000

 

Sanofi

Aflibercept

55,000

 Year 2010  

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

Merck

Safinamide

1,50,000/-

2

Wyeth

Temsirolimus

1,50,000/-

3

Quintiles

MLN0002/Placebo

20,00,000/-

4

Quintiles

BI 1744/Trial Procedure

3,00,000/-

5

Lilly

H3E-MC-JMHR

1,08,000/-

6

Lilly

H3E-EW-S124

2,00,000/-

7

Lilly

Pemetrexed

2,00,000/-

8

Bayer

Rivaroxaban/ Placebo/Warfarin

2,50,000/-

9

Bayer

Rivaroxaban

2,50,000/-

10

Bayer

Clexane/Placebo

3,50,000/-

11

Bayer

Rivaroxaban

2,50,000/-

12

Bayer

Rivaroxaban

2,50,000/-

13

Amgen

AMG-706

1,50,000/-

14

Amgen

AMG-479/AMG102

1,50,000/-

15

Bristol Myers

Brivanib alaninate/ Sorafenib

2,50,000/-

16

Sanofi

AVE005/Placebo

1,50,000/-*

17

Sanofi

AVE005/Placebo

1,50,000/-

18

Sanofi

AVE005/Placebo

2,00,000/-

19

PPD

XL-184/Placebo

10,00,000/-

20

Pfizer

Sitaxsentan/Placebo

1,50,000/-

21

Pfizer

Sitaxentan/Placebo/Sildenafil

2,25,000/-

22

Pfizer

Axitinib

1,50,000/-

 

 

 

 

 *Compensation remained unpaid as whereabouts of the legal heir could not be located by the Investigator and his team inspite of their best efforts

Year 2011

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

Apothecaries

Moxifloxacin or Placebo

2,16,000/-

2

Fresenius

Paclitaxel Nanoparticle

1,80,000/-

3

Fresenius

Paclitaxel Nanoparticle

1,35,000/-

4

Icon

CS-7017, Erlotinib

2,02,500/-

5

Icon

CS-7017, Erlotinib

2,70,000/-

6

Icon

UT-15C SR

1,80,000

7

Lambda

Amphotericin B Lipid Suspension for injection

2,00,000

8

Pfizer

AG-013736 Axitinib Tablets

1,50,000/-

9

Pfizer

Tascotinib/Placebo

5,00,000/-

10

Sanofi

Cabazitaxel

1,00,000/-

11

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

12

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

13

Sun Pharma

Docetaxel   Nano-dispersion

3,00,000/-

14

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

15

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

16

Veeda

MT 102/Placebo

50,000/-

Year 2012  

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

BMS

Brivanib

5,00,000/-

 

2

BMS

Belatacept

 2,00,000/-

 

3

BMS

Brivanib

3,72,637/-

4

Daichii- Sankyo Pharma

DU176b

2,19,447/-

5

Quintiles

DU-176b or Warfarin

5,26,638/-

6

Novartis

Aliskiren vs Enalapril

2,50,000/-

7

SUN

Docetaxel concentration Nano-Dispersion

50,000/-

8

Manipal

TRC4186/Placebo

4,38,600/-

9

Boehringer

BI 10773

5,00,000/-

10

PPD

Albiglutide

1,00,000/-

11

George

Aleglitazar

5,23,845

12

Parexel

LA294LY2127399

2,00,000

13

Piramal

P2745

1,36,028

14

Biogen Idec

BIIBo17

7,99,000

15

Astra Zeneca

AZD8931/Arimidex

9,62,475

16

Novartis

Vidagliptin

1,50,000

 

NOTE ON CLINICAL TRIALS IN INDIA

1. Research in the area of drug discovery leads to newer, safer and more efficacious drugs being made available in the country. Clinical trials are the only way of establishing the safety and efficacy of any new drug before its introduction in the market for human use. Clinical trials(with safeguards) are necessary for introduction of new drugs for a country like India, considering its disease burden and emergence of new variants of disease.

2. Clinical trials are, therefore, essential component of drug discovery research.  In order to generate adequate evidence to establish safety and efficacy of any substance for any specific indication, it is necessary that over and above all in vitroin vivo, and ex vivoexperimentations, the product is also administered to healthy volunteers and patients and clinically studied under a well-defined protocol to establish the safety and efficacy of a new drug.  This is a highly knowledge intensive activity generally carried out in international programmers.

3. The Drugs & Cosmetics Act, 1940 contains enabling provisions for regulating and ensuring quality, safety and efficacy of drugs and, therefore, contains inherent enabling powers for regulating the clinical trials. Accordingly, under the inherent plenary powers vested in the Act, necessary rules, procedures and guidelines have been framed under the Drugs and Cosmetics Rules, 1945. 

4. Regulatory provisions for conducting clinical trials in the country are prescribed under Rule-122DA, 122DAA, 122DAB, 122DAC. 122DD. 122E and Schedule Y to the Drug and Cosmetics Rules, 1945. The Clinical trial can be initiated only (i) after permission from the Drugs Controller General (India) [DCG(I)], (ii) approval from respective Ethics Committee and (iii) mandatory registration on website www.ctri.in being maintained by ICMR before the enrolment of the first trial participant for the clinical trial.

5. To ensure transparency in approval of proposals for conduct of clinical trials for drugs by the DCG(I), twelve New Drug Advisory Committees (NDAC) consisting of experts from the government medical colleges and eminent institutions from all over the country have been constituted.  Fresh applications of clinical trial proposals of new drug substances excluding investigational new drugs (INDs) are being evaluated by these Committees. For INDs, two separate expert committees have similarly been constituted. Similarly, for medical devices, six Medical Device Advisory Committees (MDAC) have been constituted.

6. The number of clinical trials permitted by DCG (I) in the last three years are as under:

Year

Number of clinical trial permissions granted

2010

529

2011

283

2012

253

7. As on 20-03-2013, as per the information available in www.clinicaltrials.gov of National Institute of Health, United States of America (USA), a total number of 1,42,239 clinical trials of different countries worldwide were registered.  Out of these, 67,881 are from USA, 38,473 from Europe, 10,702 from Canada, 2,645 from Japan.  Only 2,178 clinical trials were registered from India.

8. The Serious Adverse Events (SAEs) of death may occur during clinical trials due to various reasons. These deaths could be due to life-threatening diseases like cancer, cardio-vascular conditions like congestive heart failure / stroke and other serious diseases etc. Thus, all deaths during clinical trials may not be due to clinical trials. The number of SAEs of death in clinical trials, the number of deaths attributable to clinical trials and the number of cases, wherein compensation has been paid since 2005 are as follows:

Year

Total SAEs of Death

Death related to Clinical Trials

Compensation paid

2005

128

5

5

2006

137

2

0

2007

136

4

4

2008

288

8

7

2009

637

16

13

2010

668

22

21

2011

438

16

16

2012

436

16

16

In one case of 2010 the compensation remained unpaid as whereabouts of the legal heir could not be traced by the investigator and his team in spite of best efforts. The details of compensations paid are attached as Annexure.

9. Several steps have been taken by the Government, as follows, to strengthen the clinical trial approval procedures and their monitoring mechanism to ensure that safety, rights and well-being of clinical trial subjects are protected:

  •  12 New Drug Advisory Committees (NDAC) consisting of leading experts mostly from the Government medical colleges and institutes from all over the country have been constituted to advise the Central Drugs Standard Control Organisation (CDSCO) in matters related to approval of clinical trials and new drugs.
  • Applications of Investigational New Drugs (IND) i.e, New Drug Substances which have never earlier been used in human beings are evaluated by an IND Committee, chaired by the Director General, Indian Council of Medical Research (ICMR).
  • Registration of clinical trial in ICMR’s registry at www.ctri.in has been made mandatory.
  • Guidelines for conducting inspection of clinical trial sites and sponsor / Clinical Research Organizations (CROs) have been prepared.
  • Proposals to amend the toxicity study data requirements for  approval of clinical trial / new drugs to make it harmonized with the international guidelines have been approved by Drugs Technical Advisory Board (DTAB).

10.There have been several court cases in which issues relating to the deficiencies in the present legal provisions, safety of trial participants, death of trial participants, compensations for injury and death occurring in clinical trials, etc have been raised. Currently, the Hon’ble Supreme Court is hearing these matters in the Public Interest Litigation W.P.(C) No.33/2012 - Swasthya Adhikar Manch, Indore vs Union of India.          In the hearing of the matter on the 3rd January 2013, the Court directed that the clinical trials of new chemical entity shall be conducted strictly in accordance with the procedure prescribed in Schedule ‘Y’ of Drugs & Cosmetics Act, 1940 under the supervision of the Secretary, Health & Family Welfare. Accordingly, an Apex Committee under the chairmanship of the Secretary, Health & Family Welfare, with Secretary, Health Research-cum-Director General, Indian Council of Medical Research, and the Director General Health Services, has been constituted to monitor the approval and conduct of clinical trials.  In this connection, another Expert Committee under the chairmanship of Director General Health Services has also been constituted to assist the Apex Committee.

11. To further strengthen the regulatory provisions for approval of conduct of clinical trials and safety and well-being of trial participants, the Ministry of Health & Family Welfare has incorporated the following amendments recently in the Drugs & Cosmetics Rules, 1945:

A. Amendment vide Gazette Notification G.S.R. 53(E) dated 30-01-2013 specifying procedures to analyse the reports of Serious Adverse Events occurring during clinical trials and procedures for payment of compensation in case of trial related injury or death as per prescribed timelines as under:

I  Insertion of a new Rule 122DAB relating to compensation in case of injury or death during clinical trials.

(a)  As per the Rule, in the event of injury of the trial participant, he/she shall be provided free medical management by the sponsor or his representative as long as required.

(b)  In the event of injury or death due to following reasons which are considered as clinical trial related injury or death, the Sponsor or his representatives shall provide financial compensation for the injury or death.

  • Adverse effect of investigational product(s);
  • Violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;
  • Failure of investigational product to provide intended therapeutic effect;
  • Use of placebo in a placebo-controlled trial;
  • Adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
  • For injury to a child in utero because of the participation of parent in clinical trial;
  • Any clinical trial procedures involved in the study.

 II. Expansion of responsibilities of Sponsor, Investigator and Ethics Committees to ensure that the report of Serious Adverse Events (SAEs) including deaths are reported, analysed within the prescribed timelines and in case of clinical trial related injury or death, compensation are paid as per the prescribed procedures.

III. Insertion of definition of SAEs and detailed procedures for reporting and examination of such events in Schedule ‘Y’.

IV. The check list for trial participants’ informed consent documents have been amended to include statements describing that in the event of injury of the trial participant, he/she shall be provided free medical management as long as required and in the event of clinical trial related injury or death, the Sponsor or his representative shall provide financial compensation for the injury or death.

V.  The Format of Informed Consent Form for clinical trial participants have been amended to capture the information relating to address, qualification, occupation, annual income of the trial participant and name and address of his nominee (for the purpose of compensation in case of trial related death).  It has also been made mandatory for the investigator to hand over a copy of the patient information sheet and duly filled Informed Consent Form to the trial participant or his/her attendant.

VI.  Insertion of a separate Appendix XII related to compensation in case of injury or death during clinical trials in Schedule ‘Y’.  The Appendix prescribes the detailed procedures for examination of SAE reports including deaths and payment of financial compensation in case of trial related injury or death as per the prescribed timelines.

As per the procedures:-

(a)  Investigator shall report all SAEs to the DCG (I), Sponsor or his representative and the Ethics Committee within 24 hours of their occurrence.

(b)  In case of death, an independent Expert Committee constituted by DCG (I) shall examine the case and give recommendations to DCG (I) to determine the cause of death and also to decide the quantum of compensation, in case of clinical trial related death.  The independent Expert Committee, while examining the event, may take into consideration the reports of the Investigator, the Sponsor or his representative and the Ethics Committee.  The DCG (I), after considering the recommendations of the Expert Committee, shall determine the cause of death and decide on the quantum of compensation to be paid by the sponsor or his representative in case of trial related deaths within three months of receiving the report of SAE of death.

(c)  In case of SAEs other than death, the DCG (I), after considering the reports of the Investigator, the Sponsor and the Ethics Committee, shall determine the cause of injury and also decide the quantum of compensation to be paid by the Sponsor or his representative in case of clinical trial related injury within three months of receiving the report. The DCG(I) will have the option to constitute an Expert Committee to examine such SAEs and recommend the quantum of compensation to be paid, if any.

B. Amendment vide Gazette Notification G.S.R. 63(E) dated 01-02-2013 specifying various conditions for conduct of clinical trials, authority for conducting clinical trial inspections and actions in case of non-compliance, as under:

A new Rule 122DAC has been inserted, the salient features of which are as under:

  • Clinical trial shall be conducted in compliance with the approved protocols, requirements of Schedule Y, Good Clinical Practices (GCP) Guidelines for conduct of clinical trials in India and other applicable regulations;
  • Approval of the Ethics Committee shall be obtained before initiation for the study;
  • Clinical trial shall be registered at Clinical Trials Registry of India before enrolling the first patient for the study;
  • The Sponsor and his representative and clinical trial sites and the Investigator shall allow officers authorized by the Central Drugs Standard Control Organisation (CDSCO), who may be accompanied by an officer of the State Drug Control Authority concerned, to enter with or without prior notice into their premises and clinical trial sites to inspect, search and seize any record, data, document, books, investigational drugs, etc.
  • In case of non-compliance to the provisions of clinical trials by any Sponsor including the representative, investigators conducting clinical trial and clinical trial sites, DCG (I) can take following actions:

(a)  Reject or discontinue the study.

(b)  Suspend or cancel the clinical trial permission;

(c)  Debar the Investigator(s), Sponsor including his representative to conduct any clinical trial in future.

  1.    Amendments vide Gazette Notification G.S.R No. 72(E) dated 08-02-2013 specifying requirements and guidelines for registration of Ethics Committee, as under:

As per Rule 122DD:-

  1.               No Ethics Committee shall review and accord its approval to a clinical trial protocol without prior registration with DCG (I).
  1.              An application for registration of Ethics Committee is required to be made to DCG (I) along with detailed information about the committee as per Appendix VIII of Schedule Y, which include the Authority under which the committee has been constituted, details of qualification, etc of chairman and the members, procedures for replacement or removal of members, maintenance of records, Standard Operating Procedures (SOPs) to be followed by the committee for various activities like policy regarding training of members, prevention of conflict of interest, procedures for vulnerable population etc.
  1.             The Ethics Committee shall review and accord its approval to a clinical trial and also carry ongoing review of the trial at appropriate intervals, as specified in Schedule Y and the Good Clinical Practice Guidelines for Clinical Trials in India and other applicable regulatory requirements for safeguarding the rights, safety and well-being of the trial participants.

 

  1.             In the case of any serious adverse event occurring to the clinical trial participants during the clinical trial, the Ethics Committee shall analyse and forward its opinion as per procedures specified under Appendix XII of Schedule Y.

 

  1.              The Ethics Committee shall allow inspectors of officials authorized by the DCG (I) to inspect their facilities, records, documents etc.

 

  1.             The registration of an Ethics Committee shall be valid for a period of three years from the date of issue.

 

  1.            If the Ethics Committee fails to comply with any of the conditions of registration, DCG (I) may suspend or cancel the registration of the Ethics Committee.

12.       Since the Drugs & Cosmetics Act, 1940 does not contain specific provisions for regulating conduct of clinical trials and that the Act also does not have penal provisions therefor, specific provisions for the purpose were proposed in the Drugs & Cosmetics (Amendment) Bill, 2007 introduced in the Rajya Sabha on 21.8.2007. That Bill has been replaced by the Drugs & Cosmetics (Amendment) Bill, 2013 introduced on 29.8.2013, which contain more comprehensive provisions for the  purpose.

Annexure

             Details of compensation paid in the cases of clinical trial related deaths

Year 2005

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

 

Astra Zeneca

ZD1839

2,50,000

2

Sanofi

Heparin

3,00,000

3

Sanofi

Heparin

3,00,000

4

Roche

Bevacizumab

3,00,000

5

Siro

Methotrexate

2,55,450

Year 2007

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

Sanofi

Aflibercept

10,59,874

2

Sanofi

Aflibercept

3,00,000

3

Eli Lilly

Lisipro and Lantus

5,61,825

4

Eli Lilly

Pemetrexed

5,35,815

Year  2008

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

BMS

Ipilimumab

4,20,790

2

Bayer

Rivaroxaban

2,50,000

3

Bayer

Rivaroxaban

2,50,000

4

Bayer

Rivaroxaban

3,50,000

5

Bayer

Rivaroxaban

3,50,000

6

Bayer

Rivaroxaban

4,50,000

7

Clinigene

Bavituximab

5,00,000

Year 2009

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

 

Sanofi

AVE5026

3,00,000

 

Roche

Erlotinib

1,00,000

 

Allos Therapeutics

Pralatrexate

1,50,000

 

Boeringher Ingelheim

BIBF 1120

2,79,650

 

BMS

Apixaban

3,72,637

 

Sanofi

Aflibercept

1,13,750

 

Bayer

Rivaroxaban

3,50,000

 

Bayer

Rivaroxaban

3,50,000

 

Amgen

Denosumab

4,25,000

 

Sanofi

Aflibercept

2,00,000

 

Bayer

Rivaroxaban

3,50,000

 

Reliance

Sorafenib

5,00,000

 

Sanofi

Aflibercept

55,000

 Year 2010  

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

Merck

Safinamide

1,50,000/-

2

Wyeth

Temsirolimus

1,50,000/-

3

Quintiles

MLN0002/Placebo

20,00,000/-

4

Quintiles

BI 1744/Trial Procedure

3,00,000/-

5

Lilly

H3E-MC-JMHR

1,08,000/-

6

Lilly

H3E-EW-S124

2,00,000/-

7

Lilly

Pemetrexed

2,00,000/-

8

Bayer

Rivaroxaban/ Placebo/Warfarin

2,50,000/-

9

Bayer

Rivaroxaban

2,50,000/-

10

Bayer

Clexane/Placebo

3,50,000/-

11

Bayer

Rivaroxaban

2,50,000/-

12

Bayer

Rivaroxaban

2,50,000/-

13

Amgen

AMG-706

1,50,000/-

14

Amgen

AMG-479/AMG102

1,50,000/-

15

Bristol Myers

Brivanib alaninate/ Sorafenib

2,50,000/-

16

Sanofi

AVE005/Placebo

1,50,000/-*

17

Sanofi

AVE005/Placebo

1,50,000/-

18

Sanofi

AVE005/Placebo

2,00,000/-

19

PPD

XL-184/Placebo

10,00,000/-

20

Pfizer

Sitaxsentan/Placebo

1,50,000/-

21

Pfizer

Sitaxentan/Placebo/Sildenafil

2,25,000/-

22

Pfizer

Axitinib

1,50,000/-

 

 

 

 

 *Compensation remained unpaid as whereabouts of the legal heir could not be located by the Investigator and his team inspite of their best efforts

Year 2011

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

Apothecaries

Moxifloxacin or Placebo

2,16,000/-

2

Fresenius

Paclitaxel Nanoparticle

1,80,000/-

3

Fresenius

Paclitaxel Nanoparticle

1,35,000/-

4

Icon

CS-7017, Erlotinib

2,02,500/-

5

Icon

CS-7017, Erlotinib

2,70,000/-

6

Icon

UT-15C SR

1,80,000

7

Lambda

Amphotericin B Lipid Suspension for injection

2,00,000

8

Pfizer

AG-013736 Axitinib Tablets

1,50,000/-

9

Pfizer

Tascotinib/Placebo

5,00,000/-

10

Sanofi

Cabazitaxel

1,00,000/-

11

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

12

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

13

Sun Pharma

Docetaxel   Nano-dispersion

3,00,000/-

14

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

15

Sun Pharma

Paclitaxel Injection concentrate for Nano-dispersion

3,00,000/-

16

Veeda

MT 102/Placebo

50,000/-

Year 2012  

S. No

Sponsor

Investigational Product

Compensation paid (Rs)

1

BMS

Brivanib

5,00,000/-

 

2

BMS

Belatacept

 2,00,000/-

 

3

BMS

Brivanib

3,72,637/-

4

Daichii- Sankyo Pharma

DU176b

2,19,447/-

5

Quintiles

DU-176b or Warfarin

5,26,638/-

6

Novartis

Aliskiren vs Enalapril

2,50,000/-

7

SUN

Docetaxel concentration Nano-Dispersion

50,000/-

8

Manipal

TRC4186/Placebo

4,38,600/-

9

Boehringer

BI 10773

5,00,000/-

10

PPD

Albiglutide

1,00,000/-

11

George

Aleglitazar

5,23,845

12

Parexel

LA294LY2127399

2,00,000

13

Piramal

P2745

1,36,028

14

Biogen Idec

BIIBo17

7,99,000

15

Astra Zeneca

AZD8931/Arimidex

9,62,475

16

Novartis

Vidagliptin

1,50,000